Compounds and pharmaceutical compositions of the present invention of this type are useful in the prevention or treatment of various disorders. For instance, the substituted 4-phenyltetrahydroisoquinoline compounds and pharmaceutical compositions comprising them which are excellent inhibitors of the sodium-hydrogen exchanger (NHE) are of surprising therapeutic value in the treatment of acute and chronic disorders of the kidneys and of the intestines, disorders resulting from ischemic and/or reperfusion events, as well as those resulting from proliferative or fibrotic events,
The NHE inhibitors known in the prior art are derived, for example, from acylguanidine-type compounds (EP825178), norbornylamine-type compounds (WO0144164), 2-guanidinoquinazoline type compounds (WO0179186), benzamidine type compounds (WO0121582, WO0172742) or tetrahydroisoquinoline type-compounds (WO03048129, WO03055880). Squalamine, which has likewise been described as an NHE inhibitor (M. Donowitz et al. Am. J. Physiol. 276 (Cell Physiol. 45): C136-C144), similar to that of the acylguanidine- and norbornylamine-type compounds, does not act directly upon administration but rather via an indirect mechanism and thus does not achieve its maximum strength of action until after one hour. Since these types of NHE inhibitors have different types of mechanistic action, they are suitable, for example, in combination with those compounds of the present invention.
Clonidine, which is distantly related to the inventive compounds, is known to be a weak NHE inhibitor. However, its action on the NHE of the rat is extremely moderate at a half-maximum inhibitory concentration (IC50) of 620 μM. Instead, it has a certain selectivity for the NHE (J. Orlowski et al. J. Biol. Chem. 268, 25536). It should therefore be referred to rather as an NHE inhibitor. In addition to the weak NHE action, clonidine has a high affinity for the adrenergic alpha-2 receptor and the imidazoline receptor, which results in a strong blood sugar-lowering action (Ernsberger et al. Eur. J. Pharmacol. 134, 1, 1987).
Compounds which are similar to clonidine but have a thiophene instead of the phenyl ring are disclosed in DE1941761. The structures of formula I disclosed and claimed herein differ from existing compounds by the fusing of a thieno-substituent to the imidazole moiety of the formula I or II. This distinction allows the above-described clonidine-like undesired cardiovascular effects mediated by alpha-adrenoreceptor action to be eliminated. At the same time, as a consequence of the substitution differences, the NHE-inhibiting properties of the compounds described here are enhanced down to the micromolar and submicromolar range, while the compounds disclosed by DE1941761 exhibit only very weakly pronounced NHE-inhibiting effects, if any. For instance, the hypotensive compound described in the application DE1941761, tiamenidine, in a therapeutically utilizable concentration range, has no relevant inhibitory actions on any of the NHE subtypes investigated, NHE-1, NHE-2, NHE and NHE-5. The application WO03053434 proposes NHE inhibitors of the imidazoline type, the patent application WO 03101984 of the thiophene type and the application DE10304374 of the imidazole type.
Tetrahydroisoquinolines have been previously described as inhibitors of the sodium-hydrogen exchanger of subtype 3 (NHE-3) see WO03048129 and DE10312963. WO03055880 describes a related class of tetrahydroisoquinolinium salt compounds as NHE inhibitors. It has now been surprisingly found that the compounds of formula I described herein are also potent inhibitors of NHE and have beneficial pharmacological and pharmacokinetic properties. Thus, the compounds are notable for improved properties such as a high selectivity for the sodium-hydrogen exchanger with a negligible effect on hERG potassium channels. NHE is found in the body of various species preferentially in the bile, the intestine and the kidney (Larry Fliegel et al., Biochem. Cell. Biol. 76: 735-741, 1998), but has also been detected in the brain (E. Ma et al., Neuroscience 79:591-603).
On the basis of the NHE-inhibitory properties, the substituted 4-phenyl-tetrahydroisoquinoline compounds of the present invention as defined as the structure of formula I herein and their pharmaceutically acceptable salts are suitable for the prevention and treatment of diseases caused by the activation of or by an activated NHE. They are also useful in the treatment of diseases which are caused secondarily by the NHE-related damage.
Optionally, the NHE inhibitors described herein can be combined with other compounds which also regulate the intracellular pH environment Suitable combination comprise the formulation with other inhibitors of the enzyme group of carbonic anhydrases and inhibitors of the transport systems that carry bicarbonate ions, such as of the sodium-bicarbonate co-transporter (NBC) or of the sodium-dependent chloride-bicarbonate exchanger, and with other NHE inhibitors with an inhibitory effect on other NHE subtypes, because the pharmacologically relevant pH-regulating effects of the NHE inhibitors described herein can be enhanced or modulated thereby.
The use of compounds of the present invention relates to the prevention and the treatment of acute and chronic diseases in veterinary and human medicine.
The pharmacological effect of the compounds of the formula I is characterized in that they lead to an improvement in the respiratory drive. They can therefore be used for the treatment of impaired respiratory mechanisms and therefore useful in the treatment of acute and chronic disorders of the kidneys, intestines, as well as disorders resulting from ischemic and/or reperfusion events, as well as those resulting from proliferative or fibrotic events,
In the present invention, it has surprisingly been possible to show that the compounds of formula I, below, constitute potent inhibitors of sodium/proton exchange (NHE), especially of sub-type 3 sodium/proton exchanger (NHE).